Project Abstract The cognitive and behavioral features of autism spectrum disorders (ASD) are likely due to alterations in synaptic communication among forebrain neurons. Heterogeneity in ASD features, commonly observed in the disorder, may arise from a complex interaction of environmental and genetic risk factors that affect synaptic communication. Over the past decade the prevalence of ASD has increased from 1 in 150 to 1 in 68 making ASD the fastest growing neurodevelopmental disorder. Comparable to the prevalence of ASD, antidepressant use in pregnancy has more than tripled in recent years with selective serotonin reuptake inhibitors (SSRI) the most commonly used. To date, there is a gap in knowledge of whether prenatal SSRI exposure differentially interacts with syndromic (monogenic) or idiopathic (polygenic) risk factors for ASD. Related, unknown is whether prenatal SSRI exposure differentially affects male and female offspring. Fragile-X Syndrome, an intellectual disability syndrome caused by silencing of FMR1 gene, results in one-third of affected individuals exhibiting autistic features. A mouse model for Fragile-X exhibits some social and cognitive deficits reminiscent of ASD. The vast majority of ASD cases (~95%) are not attributed to a single gene mutation or polymorphism or to any identified environmental cause. A second model, the BTBR mouse, exhibits ASD-related behaviors and altered transcription of multiple genes that confer risk in ASD. The broad goal of this project is to use animal models to define the mechanisms by which prenatal factors contribute to cognitive and synaptic plasticity deficits related to ASD features. The proposal aims to test whether prenatal SSRI exposure in a syndromic (monogenic) mouse model and idiopathic (polygenic) mouse model of ASD exacerbates existing cognitive and synaptic plasticity phenotypes or produces new ASD-related cognitive impairments and synaptic alterations. Specific Aim 1 will determine whether prenatal SSRI exposure in Fragile-X and BTBR mice affects spatial learning and reversal learning under conditions in which feedback is certain (100% accurate) and under conditions in which feedback is uncertain (80% accurate for correct choice). Specific Aim 2 will determine in the same animals from Aim 1 whether prenatal SSRI exposure affects different aspects of hippocampal synaptic plasticity in adult Fragile-X and BTBR mice. The two aims will be integrated by determining whether there is a relationship between different learning phenomena (Aim 1) and various forms of hippocampal synaptic plasticity (Aim 2). Together, the findings from this project will advance understanding of how a prenatal risk factor interacts with genetic factors to alter synaptic and cognitive function related to ASD. Overall, this approach can provide promising new neurobehavioral endophenotypes for developing mechanistically-based neuropharmacological interventions.